M. Di Nisio

Diagnostic accuracy of D-dimer test for exclusion of venous thromboembolism: a systematic review

Summary.  Background: The reported diagnostic accuracy of the D‐dimer test for exclusion of deep vein thrombosis (DVT) and pulmonary embolism (PE) varies. It is unknown to what extent this is due to differences in study design or patient groups, or to genuine differences between D‐dimer assays. Methods: Studies evaluating the diagnostic accuracy of the D‐dimer test in the diagnosis of venous thromboembolism were systematically searched for in the MEDLINE and EMBASE databases up to March 2005. Reference lists of all included studies and of reviews related to the topic of the present meta‐analysis were manually searched for other additional potentially eligible studies. Two reviewers independently extracted study characteristics using standardized forms. Results: In total, 217 D‐dimer test evaluations for DVT and 111 for PE were analyzed. Several study design characteristics were associated with systematic differences in diagnostic accuracy. After adjustment for these features, the sensitivities of the D‐dimer enzyme‐linked immunofluorescence assay (ELFA) (DVT 96%; PE 97%), microplate enzyme‐linked immunosorbent assay (ELISA) (DVT 94%; PE 95%), and latex quantitative assay (DVT 93%; PE 95%) were superior to those of the whole‐blood D‐dimer assay (DVT 83%; PE 87%), latex semiquantitative assay (DVT 85%; PE 88%) and latex qualitative assay (DVT 69%; PE 75%). The latex qualitative and whole‐blood D‐dimer assays had the highest specificities (DVT 99%, 71%; PE 99%, 69%). Conclusions: Compared to other D‐dimer assays, the ELFA, microplate ELISA and latex quantitative assays have higher sensitivity but lower specificity, resulting in a more confident exclusion of the disease at the expense of more additional imaging testing. These conclusions are based on the most up‐to‐date and extensive systematic review of the topic area, including 184 articles, with 328 D‐dimer test evaluations.

Accuracy of diagnostic tests for clinically suspected upper extremity deep vein thrombosis: a systematic review

Summary.  Background: The best available test for the diagnosis of upper extremity deep venous thrombosis (UEDVT) is contrast venography. The aim of this systematic review was to assess whether the diagnostic accuracy of other tests for clinically suspected UEDVT is high enough to justify their use in clinical practise and to evaluate if any test can replace venography. Methods: MEDLINE and EMBASE databases were searched from inception to June 2009. Two reviewers independently evaluated study eligibility, extracted data, and assessed study quality. Results: We identified 17 papers, reporting on 793 patients. Overall, the methodological quality was poor, sample sizes were small, and large between‐study differences were observed in spectrum and design. The summary estimates of sensitivity (95% confidence interval) were 97% (90–100%) for compression ultrasonography, 84% (72–97%) for Doppler ultrasonography, 91% (85–97%) for Doppler ultrasonography with compression, and 85% (72–99%) for phleboreography. The corresponding summary estimates of specificity were, respectively, 96% (87–100%), 94% (86–100%), 93% (80–100%), and 87% (71–100%). Clinical findings, a clinical score, D‐dimer, magnetic resonance imaging, rheography and plethysmography were evaluated in one study each, involving a median number of 46 patients (range 21–214). Sensitivity and specificity ranged from 0% to 100% and from 14% to 100%. Conclusions: Methodological limitations, large between‐study differences and small sample sizes limit the evidence of tests for clinically suspected UEDVT. Compression ultrasonography may be an acceptable alternative to venography. The addition of (color) Doppler does not seem to improve the accuracy. Adequately designed studies are warranted to confirm these findings.

Prevention of catheter-related venous thrombosis with nadroparin in patients receiving chemotherapy for hematologic malignancies: a randomized, placebo-controlled study.

Summary.  Background: Hemato‐oncology patients treated with intensive chemotherapy usually require the placement of a central venous catheter (CVC). CVCs are frequently complicated by catheter‐related central venous thrombosis (CVT), which has been associated with an increased risk of pulmonary embolism and catheter‐related infection. Objectives: To determine the efficacy and safety of thromboprophylaxis with s.c. low‐molecular‐weight heparin (nadroparin) administered once daily in a randomized placebo‐controlled, double‐blind trial in patients with hematologic malignancies. Patients and methods: Consecutive patients with hematologic malignancies requiring intensive chemotherapy including autologous stem cell transplantation were eligible. The patients were randomized to receive nadroparin 2850 antifactor Xa units once daily or placebo s.c. for 3 weeks. Venography was performed on day 21 after CVC insertion. Secondary outcomes were bleeding and catheter‐related infection. Results: In total, 113 patients were randomized to nadroparin or placebo, and 87 patients (77%) underwent venography. In total, 11 venographically proven catheter‐related CVTs were diagnosed. The frequency of catheter‐related CVT was not significantly different between study groups, namely four catheter‐related CVTs in the placebo group [9%; 95% CI: 0.002–0.16] vs. seven catheter‐related CVTs in the nadroparin group (17%; 95% CI: 0.06–0.28). In addition, no difference in the incidence of catheter‐related infection or bleeding was observed between the groups. Conclusion: This study showed that the actual risk for catheter‐related CVT in patients with hematologic malignancies is lower than suggested in earlier studies in cancer patients. Although prophylactic administration of nadroparin appeared to be safe in this group of patients with a high risk of bleeding, it cannot be recommended for the prevention of catheter‐related CVT or catheter‐related infection in patients with hematologic malignancies.

Decision analysis for cancer screening in idiopathic venous thromboembolism

Summary.  Background: The SOMIT trial randomized patients with idiopathic venous thromboembolism (IVTE) and without signs of cancer at routine medical examination, to extensive screening for cancer plus 2 years of follow‐up or to just 2‐year follow‐up. Methods: The data of the SOMIT‐trial were used to perform a decision analysis. The screening tests were divided in several possible strategies. The number of detected cancer patients and the number of patients investigated further for an eventually benign condition were calculated for each strategy. The total costs for the screening strategy and for each detected cancer patient were determined. Based on the tumor type, stage, age and gender of the individual cancer patient, the difference in live years gained (LYG) was calculated between the two study groups. Results: Computed tomography (CT) of the abdomen combined with sputum cytology and mammography detected 12 of the 14 patients with cancer and had one false‐positive result. In general, screening strategies including abdominal/pelvic ultrasonography (US) or tumor markers yielded a higher number of patients needed to screen in comparison with those using abdominal/pelvic CT. Furthermore, the strategies which included colonoscopy, tumor markers, and abdominal/pelvic US were significantly more costly, had inferior LYG and higher costs per LYG, when compared with strategies using abdominal/pelvic CT. Conclusions: Despite the limitations of this analysis, the screening for cancer with a strategy including abdominal/pelvic CT with or without mammography and/or sputum cytology appears potentially useful for cancer screening in patients with IVTE. The cost‐effectiveness analysis of this strategy needs confirmation in a large trial.

D-Dimer test in cancer patients with suspected acute pulmonary embolism

Summary.  Background: The safety of a D‐dimer (DD) measurement in cancer patients with clinically suspected pulmonary embolism (PE) is unclear. Objectives: The aim of this study was to assess the accuracy of the DD test in consecutive patients with clinically suspected PE with and without cancer. Methods: The diagnostic accuracy of DD (Tinaquant D‐dimer) was first retrospectively assessed in an unselected group of patients referred for suspected PE (n = 350). Subsequently, the predictive value of the DD was validated in a group of consecutive inpatients and outpatients with clinically suspected PE prospectively enrolled in a management study (n = 519). The results of the DD test in cancer patients were assessed according to the final diagnosis of PE and the 3‐month clinical follow‐up. Results: In the first study group, DD showed a sensitivity and a negative predictive value (NPV) of 100% and 100% in patients with cancer and 97% and 98% in those without malignancy, respectively. In the validation cohort, the sensitivity and NPV of DD were both 100% (95% CI 82%–100% and 72%–100%, respectively), whereas in patients without malignancy, the corresponding estimates were 93% (95% CI 87%–98%) and 97% (95% CI, 95%–99%), respectively. The specificity of DD was low in patients with (21%) and without cancer (53%). Conclusions: A negative DD result safely excludes the diagnosis of PE in patients with cancer. Because of the low specificity, when testing 100 patients with suspected PE, a normal DD concentration safely excludes PE in 15 patients with cancer and in 43 patients without cancer.

Diagnosis and treatment of incidental venous thromboembolism in cancer patients: guidance from the SSC of the ISTH.

Modern computer tomography (CT) with its higher sensitivity and resolution has increased the detection of incidental venous thromboembolism (VTE) in the venous and pulmonary vasculature during routine imaging for cancer staging and response assessment [1]. As a result, up to half of all VTEs diagnosed in oncology centers are incidental [1-5]. Although widely accepted, the diagnosis of incidental VTE is made without using the standard imaging studies required for confirming the presence of symptomatic VTE (i.e. compression ultrasonography for deep vein thrombosis [DVT] and CT pulmonary angiography [CTPA] or ventilation/perfusion lung scan for pulmonary embolism [PE]). The accuracy and reliability of staging imaging in making a diagnosis of DVT or PE have not been established. This article is protected by copyright. All rights reserved

Combined use of clinical pretest probability and D‐dimer test in cancer patients with clinically suspected deep venous thrombosis

Summary.  Background: The value of the D‐dimer (DD) test in combination with the clinical pretest probability (PTP) has not been evaluated in cancer patients with suspected deep vein thrombosis (DVT), whereas this group of patients usually accounts for 10–25% of clinically suspected DVT. Methods: A cohort of 2066 consecutive patients with clinically suspected DVT was investigated. Patients were judged to be positive or negative for DVT according to the outcomes of serial compression ultrasound and a 3‐month follow‐up period with imaging test verification of the symptomatic cases. Diagnostic accuracy indices of the DD test according to the PTP score were assessed in patients with and without cancer. Results: Of the cohort, 244 (11%) were known to have cancer at presentation. A venous thromboembolic event was diagnosed in 41% of the patients with cancer and in 22% of the patients without malignancy. Among the cancer patients, 17% were considered to have a low PTP, 35% a moderate and 41% a high PTP. The negative predictive value (NPV) of the DD test was 100% (95%CI, 85–100) and 97% (95% CI, 88–99) among cancer patients with low PTP or low‐moderate PTP. In the absence of malignancy, the corresponding NPV were 98% and 97%, respectively. The specificity of the DD test progressively decreased moving from the low to the higher PTP. Conclusions: In cancer patients with clinically suspected DVT, a negative DD might be useful in excluding the diagnosis within the low or low‐moderate PTP groups. More studies are warranted to confirm these findings.

Prevention of venous thromboembolism in hospitalized medical cancer patients: guidance from the SSC of the ISTH.

Cancer patients hospitalized for an acute medical illness are at increased risk of venous thromboembolism (VTE). Pharmacological thromboprophylaxis is considered standard practice for these patients and current guidelines recommend prophylactic doses of low-molecular-weight heparins (LMWHs), unfractionated heparin (UFH), or fondaparinux in the absence of bleeding or other contraindications [1-4]. These recommendations are extrapolated from large placebo-controlled randomized clinical trials (RCTs) of VTE thromboprophylaxis in broad mixed populations of medical inpatients, none involving exclusively cancer patients or presenting efficacy and safety data for this subgroup [5-8]. Because cancer inpatients represent a unique population with increased risk of VTE and major hemorrhage, validation of the efficacy and safety of thromboprophylaxis in this group is critical. This article is protected by copyright. All rights reserved

The prognostic value of the D‐dimer test in cancer patients treated with and without low‐molecular‐weight heparin

adsorption of the rFVIII protein to the inner surface of the tubing and bag. This effect is slightly different for the sucroseformulated product evaluated here compared with the albumin-formulated product studied by Hurst et al., and could be explained by the presence of albumin competing during the initial adsorption/saturation process. The results obtained under the above-mentioned experimental conditions suggest adequate stability when rFVIII-FS is delivered under in vitro conditions approximating continuous infusion. In a clinical situation, the minimal binding of protein to the infusion tubing at the start of continuous infusion would probably not alter the plasma FVIII concentration, as such patients would receive a bolus injection of FVIII prior to the initiation of continuous infusion. These results provide a preliminary basis for the use of Kogenate FS in clinical trials, and situations requiring prolonged and/or intensive hemostatic treatment. Conflicts of interest disclosure

Safety and efficacy of low‐dose fondaparinux (1.5 mg) for the prevention of venous thromboembolism in acutely ill medical patients with renal impairment: the FONDAIR study

Summary.  Background:  Renal impairment is common, affecting around 40% of acutely ill medical patients, and is associated with an increased risk of both venous thromboembolism (VTE) and bleeding. The clinical benefit of effective thromboprophylactic strategies may be outweighed in these patients by an excessive rate of hemorrhage.